Using heterotopic cardiac transplants in rabbits as our model, we have demonstrated that following transplantation, and antibody that binds to myocardial tissue appears in the serum of the experimental animal. This antibody binds to both recipient and donor hearts and is directly affected by immunosuppressive therapy. This antibody correlates well with histological evidence of rejection, Immunofluorescent staining of donor and recipient hearts reveals the presence of antibody producing mononuclear cells and deposits of IgG in the donor hearts only. It is our intention now to further explore the cellular and humoral reactions in this experimental system. Both serum antibody and antibody eluted from donor hearts, as well as sensitized lymphocytes, will be tested for their ability to kill monolayers of embryonic cardiac tissue. The effect of antibody (blocking or enhancing) on the ability of sensitized lymphocytes to exert their cytotoxic effect will also be examined. The role of certain complement components in the initiation of the rejection process will be studied by inducing relative C3 deficiency in certain recipient animals. The effect of presensitization of recipient animals with bacterial membranes known to cross-react with heart tissue will also be investigated. Hopefully, these studies will shed further light on the relative role of cellular and humoral reactions in the rejection of this organ. An ultimate aim of the project would be the specific induction of tolerance to the implanted organ. We plan to use two main approaches to this problem. The first will involve the induction of tolerance via the use of tolerogenic doses of cardiac or bacterial antigens prior to organ implantation. The second will involve the removal of specific antigen- sensitive cells after organ implantation.